Studies in SARP have shown that adult and pediatric asthma patients can be grouped into different phenotypes on a spectrum of disease severity. However, there remains a clear need to validate and improve the fidelity of phenotype designation, establish its stability over time, and determine the critical variables that may contribute to phenotype progression. We have shown that patients with severe asthma have more extensive air trapping compared to those with non-severe asthma. Airway imaging has shown increased heterogeneous regional ventilation defects and air trapping. Some of these defects are persistent, while others can be provoked with virus-induced exacerbations or bronchial challenge and recur in the same general areas on repeated challenge, suggesting localized airway dysfunction. In preliminary studies, inflammatory parameters tended to be more prominent in segments that showed ventilation defects on imaging. In other studies, we showed that children with recurrent severe wheezing episodes have lower lung function later on, an observation supported by published studies on adult and pediatric patients with asthma. Therefore, we hypothesize that severe asthma exacerbations, in some patients, are associated with incomplete recovery and activation of airway inflammatory cells in a regional distribution. This leads to enhanced airway injury with airway dysfunction as reflected by ventilation defects and air trapping, and a more generalized increase in disease severity. To evaluate this hypothesis we propose the following specific aims: 1. To refine phenotyping of severe asthma using new variables from multiple domains in a large longitudinal patient cohort; and to determine the contribution of severe asthma exacerbations to disease progression. 2. To characterize regional obstructive patterns at baseline and their relationship to changes in pulmonary function; and to determine how incremental changes in regional airway dysfunction after recovery from asthma exacerbation may contribute to severe asthma. 3. To determine the contribution of established and novel biomarkers (YKL-40, vWF, & P-selectin), in refining the severe asthma phenotypes and the role of inflammatory cells in causing airway injury following virus-induced asthma exacerbations with subsequent development of ventilation defects. We have the necessary resources, expertise and commitment to successfully execute these studies and to better define severe asthma phenotypes with the goal of improving patient outcomes. RELEVANCE: The novel information gained from these studies will inform new definitions and phenotyping of severe asthma, and pave the way for exploring potential new paradigms for preventing disease progression and incorporating phenotype-informed treatment modalities that would positively impact patient outcome.